新型选择性雄激素受体降解分子的发现、优化及抗前列腺癌研究

前列腺癌（Prostate Cancer）是威胁男性健康的常见肿瘤之一，而雄激素受体（AR）是前列腺癌药物治疗的关键靶点。当前临床应用第二代AR拮抗剂对去势抵抗前列腺癌（CRPC）疗效显著，但耐药性突变及AR可变剪接体表达导致CRPC产生严重耐药问题，选择性雄激素受体降解分子 (SARDs) 有望成为新一代AR拮抗剂。通过前期的模型构建以及筛选，我们发现新型选择性雄激素受体降解分子Z15。Z15结构新颖、合成简便，具有独特作用机制，可有效克服二代AR拮抗剂的耐药性问题。本申请研究拟在Z15结构的基础上进行结构优化，并结合理性分子设计、生物测活等技术手段，寻找活性更好、选择性更高的候选药物分子，进而开展作用机制研究及初步成药学研究。项目的实施，将为前列腺癌治疗提供新策略，并促进选择性诱导降解小分子药物研发。

Prostate cancer is one of the most common tumors that threaten male’s health, and androgen receptor (AR) is the critical target in the treatment of prostate cancer. Currently clinical used second generation AR antagonists show significant effects on castration resistant prostate cancer (CRPC), while the mutation of drug resistance and the expression of AR variable splices lead to the serious resistance of CRPC. Selective androgen receptor degraders (SARDs) are promising to become a new generation of AR antagonists. Based on the previous screening work, we found a novel SARDs molecule termed as Z15. Z15 has novel structure, simple synthesis and unique mechanism, which can effectively overcome the resistance of second generation AR antagonists. Herein, based the structure of Z15, we plan to perform structural optimizaion, following by combining with rational molecular design, bioassay as well as other technologies to find more active and more selective candidates. Further, mechanism studies and preliminary pharmaceutical research will be carried out. In general, the achievement of the research work in the proposal will provide a new strategy for prostate cancer treatment and promote the development of selective induced degradation of small molecule drugs.